Alisertib in Combination with Weekly Paclitaxel in Patients with Advanced Breast Cancer or Recurrent Ovarian Cancer: A Randomized Clinical Trial

Gerald Falchook, Robert L. Coleman, Andrzej Roszak, Kian Behbakht, Ursula Matulonis, Isabelle Ray-Coquard, Piotr Sawrycki, Linda R. Duska, William Tew, Sharad A Ghamande, Anne Lesoin, Peter E. Schwartz, Joseph Buscema, Michel Fabbro, Alain Lortholary, Barbara Goff, Razelle Kurzrock, Lainie P. Martin, Heidi J. Gray, Siqing FuEmily Sheldon-Waniga, Huamao Mark Lin, Karthik Venkatakrishnan, Xiaofei Zhou, E. Jane Leonard, Russell J. Schilder

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17 Scopus citations

Abstract

Importance: There is an unmet medical need for the treatment of recurrent ovarian cancer, and new approaches are needed to improve progression-free survival (PFS) and overall survival. Objective: This phase 1/2 study evaluated the activity of alisertib in combination with weekly paclitaxel in patients with breast (phase 1) and ovarian cancer (phase 1 and phase 2). Design, Setting, and Participants: An open-label phase 1 and randomized phase 2 clinical trial conducted from April 16, 2010, for phase 1 and March 28, 2012, to August 12, 2013, for phase 2 was conducted at 33 sites (United States, France, and Poland). Data are reported from a cutoff date of August 12, 2014, with a median duration of follow-up of 7.2 months in the alisertib plus paclitaxel arm and 4.6 months in the paclitaxel arm. A total of 191 women with advanced breast (phase 1 only) or recurrent ovarian cancer were enrolled, including 142 patients randomized to alisertib plus paclitaxel (n = 73) or paclitaxel alone (n = 69) in the phase 2 study. Interventions: Patients were randomized 1:1 stratified by platinum-free interval (refractory, 0-6 months, 6-12 months) and prior weekly taxane treatment (yes, no) to receive alisertib 40 mg twice per day orally and 3 days on and 4 days off for 3 weeks, plus paclitaxel (60 mg/m 2 intravenously, days 1, 8, and 15), or weekly paclitaxel 80 mg/m 2 intravenously in 28-day cycles. Main Outcomes and Measures: Primary endpoint was PFS; primary efficacy analysis and safety analysis used modified intention to treat (mITT) population (all randomized patients who received ≥1 dose of study drug). Results: The median age for the 191 patients enrolled in phase 1 was 59 (range, 29-75) years. The median age for the 142 patients enrolled in phase 2 was 63 (range, 30-81) years for patients receiving alisertib plus paclitaxel and 61 (range, 41-81) years for patients receiving paclitaxel. At data cutoff, 107 (75%) patients had a documented PFS event; 52 (71%) in the alisertib plus paclitaxel arm, and 55 (80%) in the paclitaxel arm. Median PFS was 6.7 months with alisertib plus paclitaxel vs 4.7 months with paclitaxel (HR, 0.75; 80% CI, 0.58-0.96; P =.14; 2-sided P value cutoff =.20 to be considered worthy of further investigation). Drug-related grade 3 or higher adverse events were reported in 63 (86%) vs 14 (20%) patients in the alisertib plus paclitaxel and paclitaxel arms, including 56 (77%) vs 7 (10%) neutropenia, 18 (25%) vs 0 stomatitis, and 10 (14%) vs 2 (3%) anemia; 54 (74%) vs 17 (25%) had adverse events leading to dose reductions. Two patients died during the study (1 in each arm); neither death was considered related to study drug. Conclusions and Relevance: The primary endpoint, PFS, significantly favored alisertib plus paclitaxel over paclitaxel alone. Further investigation is warranted. Trial Registration: ClinicalTrials.gov identifier: NCT01091428.

Original languageEnglish (US)
JournalJAMA Oncology
Volume5
Issue number1
DOIs
StatePublished - Jan 2019
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Falchook, G., Coleman, R. L., Roszak, A., Behbakht, K., Matulonis, U., Ray-Coquard, I., Sawrycki, P., Duska, L. R., Tew, W., Ghamande, S. A., Lesoin, A., Schwartz, P. E., Buscema, J., Fabbro, M., Lortholary, A., Goff, B., Kurzrock, R., Martin, L. P., Gray, H. J., ... Schilder, R. J. (2019). Alisertib in Combination with Weekly Paclitaxel in Patients with Advanced Breast Cancer or Recurrent Ovarian Cancer: A Randomized Clinical Trial. JAMA Oncology, 5(1). https://doi.org/10.1001/jamaoncol.2018.3773